Nuclear receptors (NRs) represent the largest family of ligand-dependent eukaryotic transcription factors transforming extra- and intracellular signals into cellular responses by triggering the transcription of target genes. The androgen receptor (AR) is a member of the NR family and its role is to modulate the biological effects of the endogenous androgens, testosterone (tes) and dihydrotestosterone (DHT). The AR plays many roles during male foetal and pubertal development as well as secondary sexual characteristics such as muscle and bone mass, strength, fat distribution and spermatogenesis. Androgen-dependent cells are dependent on activation of the androgen receptor (AR) for cell growth. Under normal circumstances, androgen natural hormones (tes and DHT) bind to the ligand binding pocket (LBP) placed at ligand-binding domain of the AR. The AR, in dimeric form, is then transferred into the nucleus, where it binds to androgen response elements (AREs). Nuclear co-activators and co-suppressors also bind to this complex, modulating the degree of transcription and cellular activation.
Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. Similarly, excessive androgen concentrations can lead to a number of clinical pathologies.
Male pattern hair loss is the most common cause of balding. The pathogenesis involves androgen, and in particular dihydrotestosterone, binding to androgen receptors in the dermal papilla of sensitive hair follicles. Androgens also play pathogenic roles in acne mainly through stimulation of lipogenesis in sebaceous glands in a complex manner. Additionally, hirsutism is characterised by excessive coarse terminal hairs in a male-like pattern and is due to increased androgen production or increased sensitivity of androgen receptors. Polycystic ovary syndrome (PCOS) is by far the commonest cause of hirsutism.
Synthetic androgens and anti-androgens have therapeutic value in the treatment of various androgen dependent conditions, from regulation of male fertility to prostate cancer (PCa). The traditional ligand focussed treatment regime for PCa is reliant on the blockage of tes and DHT by AR LBP antagonists binding and thereby not allowing the activation of AR.
Anti-androgens traditionally act by two primary mechanisms: inhibition of hormone (androgens) binding to the androgen receptor, so-called androgen ablation therapy (AAT), and inhibition of androgen-independent activation of the receptor. The latter mechanism occurs via several pathways, including inhibiting nuclear co-activators, activating co-suppressors, and inhibiting transcription of a variety of androgen regulated genes.
A number of LBP anti-androgens have been demonstrated clinically as an effective therapy for the treatment of prostate cancer, including cyproterone acetate, flutamide and bicalutamide. These compounds compete with tes and its powerful metabolite, dihydrotestosterone (DHT) for binding to androgen receptors in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer cells to grow. Flutamide is an anti-androgen drug which was primarily used to treat prostate cancer. Flutamide may also be used to treat excess androgen levels in women. Bicalutamide is an oral non-steroid al anti-androgen for prostate cancer, which has largely replaced flutamide due to a better side-effect profile. Nilutamide is an antiandrogen medication used in the treatment of advanced stage prostate cancer. Nilutamide blocks the AR preventing its interaction with testosterone. Because most prostate cancer cells rely on the stimulation of the androgen receptor for growth and survival, nilutamide can prolong life in men with prostate cancer.

These anti-androgens exhibit good efficacy in many cases, however, prolonged LBP-targeting can often lead to androgen resistance. Recurrence occurs after a short period of response as they have partial agonist activities at high concentrations in vitro.
The structure of the NRs is extensively documented, and in general NRs share the following common organisation: a variable amino-terminal activation function domain (AF-1), a highly conserved DNA-binding domain (DBD), a hinge region which contains the nuclear localisation signal, a conserved C-terminal ligand-binding domain (LBD) comprising a 12 helical structure that encloses a central ligand binding pocket (LBP) and a second activation function domain (AF-2) which is located at the carboxy-terminal end of the LBD and which mediates ligand-dependent transactivation.
Traditional nuclear receptors (NRs) drug discovery has been focused at the heart of the C-terminal 12-alpha helical ligand binding domain (LBD), the ligand binding pocket (LBP), where natural ligands bind and drive conformational changes that indirectly modulate protein-protein interactions at non-LBP docking sites that are necessary for NR transcriptional activity. In response to the ligand binding to the LBP, the hydrophobic surface activation function 2 (AF-2), involving helices 3, 4, 5 and 12, is generated for the recruitment of coactivator proteins that ultimately have consequences in NR functional activity. In a recent work, an additional secondary function site called binding function 3 (BF-3) has been reported on the surface of the AR that could also play a relevant role in the allosteric modulation of the AF-2 (Estebanez-Perpina E, Arnold L A, Nguyen P, Rodrigues E D, Mar E, et al. (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proc. Natl. Acad. Sci. USA 104:16074-16079). Alternative AR targeting through this regulatory interfaces (AF-2 and BF-3) has gained a great deal of attention over the past decade. The need of such approaches arises by the limitation of the currently marketed LBP-acting antiandrogens regarding their applications, especially in. for example, castrate resistant prostate cancer.
Notwithstanding the state of the art, novel anti-androgenic agents that exhibit no agonistic activity, so called “AR pure antagonists” are strived for. Inhibition of the transcriptional activity of the NRs by directly blocking critical receptor:coactivator interactions provides an attractive opportunity to find non-steroidal, small molecules that are tissue-selective and elicit the desired activity with reduced side effects, whilst at the same time exhibiting no partial agonist behaviour.